Irradiated products of 3h-1,4-benzodiazepine 4-oxides

ABSTRACT

1,3,-BENZOXADIAZOCINES AND 1,2-DIHYDRO-QUINOXALINES ARE USEFUL AS ANTI-INFLAMMATORY AGENTS, ANTI-CONVULSANTS AND ANTI-BACTERIAL AGENTS AND METHODS FOR THEIR PRODUCTION.

.to ultra-violetlig ht.,.-

r PllWipw ofth e; present iny States Ren 01 'j .5 3",555,o22'f f a .IRRADIATED PRODUCTS or 3H-1,4-

- BENZODIAZEPINE 4-0XIDES cage Francis Field, West Caldwell, n Leo Henr k Sternbach, Upper Montclair, N.'J., assignors to Halfniann-La Roche Inc., Nutley, N..I., a corporation of "NewJei-sey' :j No Drawing. Filed Sept. .5, 1967,Ser. No. 665,293 I ::'Int.1Cl.C07d 51/78 a US. Cl. 260-250 1 3 Claims A sT Ac'r, or. THE DISCLOSURE ;-'1,3,6-benzoxadiazocines and i 1,2-dihydro-quinoxalines are useful as anti-inflammatory agents, 'anti-oonvulsants an'd'anthbacterial agents 'and'methods for their production'. v

i or

'I n 'aecdraa'nc with invention,"we have discovered that compounds selected from the group consisting of compounds of the formula:

and pha rmaceuticafly acceptablejsalts, l I V wherein R is selected from the group consisting of hydro- Patented Jan. 12, 1971 vention are the'acid addition salts of the novel medicinally valuable 1,3,6-benzoxadiazocines' and -1,2-dihydro-qu-inoX- alines of Formulae I and II above. More particularly, the j compounds of Formulae land 11 above, form acid addition salts with pharmaceutically acceptable organic and inorganic acids, such as hydrochloricacid, hydro-- bromic acid, nitric acid, sulfuric acid, acetic acid,'formic acid, succinic acid, maleic acid,- p-toluene sulfonic' acid and the like. 1 DETAILED DESCRIPTION OF THE INVENTION The numbering of the benzoxadiazocine ring system is shown in Formula I above, for the purposes of convenience. Also the numbering of the quinoxalinering system is shown in Formula II above, for .the' purposes of convenience. 1

As used herein, the term lower alkyl includes bothstraight and branched chain alkyl groups having from .1. to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, and the like. In like manner-the. term lower alkoxy refers to both straight and branched chain alkoxy I radicals, containing 1 to 7 carbon atoms such as methoxy,

ethoxy, butoxy, etc. The term halogen includes bromine, chlorine, fluorine, and iodine.

In the preferred embodiment of 1,3,6-benzoxadiazocines of Formula I above, R is a substituent in the 9'-position and is either halogen, trifluoromethyl, or nitro. In

the preferred embodiment of the 1,2-dihydro-quinoxalines of Formula H above, R is a substituent in the 7-position and'is a halogen. When R'is a halogen, the preferred halogen is chlorine. In the 1,3,6-benzoxadiazocines of Formula I above, R is preferably hydrogen or a lower gen, lower alkyl halogen, nitro, and trifiuoromethyl;

R is selected from the group -NR R hydrogen, and lower alkyl; R is selected from the group consisting of hydrogen, lower alkyl and lower alkoxy-lower alkyl; R is selected from the group consisting of phenyl, lower alkyl substituted phenyl, nitro substituted phenyl, halo substituted pheny l and pyridyl; and R and R are selected from the group consisting of hydrogen and lower alkyl and R;- and" Rstakentogether with their attachednitrogen atom ,form a 5 to 6 membered :i h e o yc ring;-v 31' i are active as anti-inflammatory agents, anti-convulsants and anti-bacterial agentsgsuch as disinfecting agents against such micro-organisms as D. pneumoniae and E. insidiasa.

Compounds of Formulae {Land 11 above, are prepared in accordance with this invention by subecting 3H- 1,4

y o wherein R, R R and R are as above,

q include W alkyl radical such as methyl or ethyl. When R is a lower alkoxy-lower alkyl, the R is preferably methoxy-methyl, methoxy-ethyl or ethoxy-methyl.

In accordance with the preferred embodiment of this invention, R is an amino radical of the formula:

and piperidino.

.In thepreferred embodiment of compounds of Forniulae I and II above, R is either phenyl,.2-pyridyl, or phenyl substituted on the 2-position with a halo group such as chlorine or fluorine.

The 1,3,6-benzoxadiazocines of Formula I, and the 1,2-dihydro-quinoXalines of Formula II are useful as anti-inflammatory agents and anti-convulsants. The compounds of Formulae I and II, as. wellas their pharrnaceutically acceptable acid addition salts, areused in the form of conventional pharmaceutical preparations, which contain said compounds'in connection with conyentional pharmaceutical organic'or inorganic materials suitable for internal administration. The-pharmaceutical compositions containing the compounds of Formulae I and-II above, as well as their pharmaceutically acceptable acid addition salts, can be administered parenterally or orally. Dosage's'can be adjusted to individual requirements, for example, these compounds can be administered dosageiorms, such as. tablets, .dragees, suppositories, capsules or in conventional liquid dosage forms, such as solutions, suspensions or' emulsions. The pharmaceutical compositions can be submitted to conventional pharmaceutical expedients, such as sterilization and/or can contain pharmaceutical additives, such as preservatives, stabilizing agents, wetting agents, emulsifying agents, salts for adjusting the osmotic pressures, buffers or the like. It also can contain other therapeutically useful materials.

The anti-convulsant activity of the compounds of Formulae I and II above, can be seen from the maximal electroshock test in mice which is described in Behrens, Arch. Expt. Path, and Pharm. 140: 237, 1929. A compound such as 9-chloro-5-methylamino-2-phenyl-4H- 1,3,6-benzoxadiazocine has an ED of 692 mg./kg. p.o. as measured by the maximal electroshock test.

The use of the compounds of Formulae I and II as anti-inflammatory agents can be seen from the yeast inflammed foot test which is described in Randall et al., Arch. Int. Pharmacodyn. 111: 409, 1957. A compound such as 1-benzoyl-7-chloro-1,2-dihydro-3-methylaminoquinoxaline has an ED of 100 ing/kg. p.o. as measured by the yeast inflammation foot test, whereas acetyl salicylic acid, a common anti-inflammatory agent, has an ED of 400 mg./kg. p.o. as measured by this same test.

The 1,3,6-benzoxadiazocines of Formula I above, and the 1,2-dihydro-quinoxalines of Formula II above, are useful in various cleansing protective coatings and other product formulations to provide inhibition of microbial growths. These compounds of Formulae I and II above, can be applied to surfaces to destroy microbial growth by means of organic solvents such as ethanol. Furthermore, the compounds of Formulae I and II above, can be utilized in the formulation of commercial detergents such as laundry or dish-washing detergents. The compounds of Formulae I and II above, can be utilized with any conventional anionic or nonionic detergents.

The compounds of Formulae I and II above are elfective antibacterial agents against a variety of micro organisms. For example, the minimum inhibitory concentrations (MIC) in mcg./ml. determined in vitro by the serial broth dilution method utilizing a trypticase soy broth for 9-chloro-5-methylamino-2-phenyl 4H 1,3,6- benzoxadiazocine was 39 for D. pneumoniae and 2,500 for E. insidiosa. The minimum inhibitory concentration in mcg./ml. for 1-benzoyl-7-chloro-1,2-dihydro-3-methylamino-quinoxaline measured by the same test was 156 for S. pyogenes, 15.6 for D. pneumoniae, 31.25 for E.

i/zsidiosa, and 312.5 for S. agalictiae.

The compounds of Formulae I and II above, can be prepared from compounds of the Formula III above, by means of subjecting the compounds of the Formula III above, to irradiation with ultraviolet light. In carrying out this reaction, any conventional ultraviolet light source can be utilized. This reaction is carried out in the presence of an inert organic solvent. Any conventional inert organic solvent can be utilized. Typical solvents which can be utilized in accordance with this invention include, benzene, ethanol, toluene, tetrahydrofuran, hexane, pentane, diethyl ether. In this reaction, temperatures of from 10 C. to 150 C. can be utilized. Generally, it is preferred to carry out this reaction at the reflux temperature of the solvent. The irradiation of the compound of Formula III above, to produce compounds of the Formulae I and II above, is generally carried out by exposure to ultraviolet light for a period of from 1 hour to 3 days. The use of longer times produces a better conversion of the compounds of Formula III above, to compounds of Formulae I and II above. Longer time periods than 3 days can be utilized if desired. Generally, irradiation times of greater than 3 days are seldom utilized since no additional beneficial results are achieved by utilizing such long exposure times.

adsorbents. Therefore, the compounds of Formula I above, can be separated from the compounds of Formula II above, by any conventional .solvent separating means, such as fractional crystallization, etc. utilizing conventional inert organic solvents.

Furthermore, due,to the differences. in the adsorption rates of the compounds of Formulae I and 11 above, on conventional adsorbents, compounds of Formula I above can be separated from compounds of Formula II above by the use of any conventional adsorbing procedures, such as chromatography. This procedure can utilize any con-,-

ventional adosrbing means, such as silica, alumina, fluorosil, etc.

In accordance with a preferred embodiment of this invention, R in compounds of the Formula II above, is

wherein R and R are as above,

so that compounds of the Formula II above, have the formula N N W...

R3 IV wherein R, R R R and R are as above.

The compounds of the Formula IV can be prepared from compounds of the formula:

N (1:0 fix 7 V wherein R, and R are as above,

by means of reacting the compounds of the Formula V above, with an organic amino compound of the formula:

R4 VI wherein R and R are as above,

in the presence of an acid catalyst.

of the-Formulailv. above, is carried' outinlhe presence of anwinert organic solvent. Any-conventionalinert.organic solvent, such as those mentioned hereinbefore, cana be utilized in carrying, out .this reaction. in carrying out this reaction, temperature and pressure are not critical, and

this reaction cambe eifected .at room. temperature ,.-or .be-"

low, and at atmospheric pressure or at elevated temperatures, and/or elevated pressure. Generally, it is preferred to carry out this reaction ata temperatrue qf fro mv abgut C. to about 25 C. While it is generally preferable to' utilize these low temperatures, temperatures as high as the reflux temperature of the solvent can be utilized.

The invention is further illustrated by the following examples. In the examples, all temperatures are given in degrees centigrade.

Example 1.--Photolysis of 7-chloro-2-methylamino-5- phenyl-3H-l,4-benzodiazepine 4-oxide A solution of 10 g. of 7-chloro-2-methylaminow5-phenyl-3H-1,4-benzodiazepine 4-oxide in a mixture of 0.4 l. of ethanol and 1 l. of benzene was irradiated for 18 hours with an unfiltered Hanovia 200 watt lamp. The solution was concentrated in vacuo, and the residue crystallized from ether to give a mixture of two photo isomers 9- chloro -methylamino-2-phenyl-4H-1,3,6-benzoxadiazocine and 1-benzoyl-7-chloro-1,2dihydro3-methylaminoquinoxaline. Recrystallization of a portion of this mixture three times from ethanol gave 9-chloro-5-methylamino-2- phenyl-4H-1,3,6-benzoxadiazocine as beige needles.

To a solution of 5 g. of the above mixture of 9-chloro- S-methylamino-2-phenyl-4H-1,3,6-benzoxadiazocine and 1 benzoyl-7-chloro-1,2-dihydro-3-methylaminoquinoxaline, in 125 ml. of hot ethanol was added 25 ml. of l N hydrochloric acid, and mixture was heated on the steam bath for 5 minutes. Dilution to 375 ml. with water and cooling gave 2-benzamid1o-4-chloro-2-hyd ioxyacetamlide.

The aqueous mother liquors left after separation of 2- benzamido-4-chloro-2'-hydroxyacetanilide were neutralized with concentratedammonium hydroxide to give 1- beuzoyl-7-chloro-l,2-dihydro-3-methylaminoqumoxalme.

Example 2.-4benzoyl-6-chloro-3,4-dihydro-2 methylaminoquinoxaline from 4-benz0yl-6-chloro-3,4-d1hydroquinoxalin-2 1H) -one Example 3 Per capsule, mg. 1-benzoyl-7-chloro-1,2-dihydro-3 methylamin'oquinoxaline 10 Lactose, U.'S.P. t 165 Corn starch, U.S.P. 30 Talc,U.S.P. 5

Total weight 210 A 210 mg. capsule was prepared by the following: .1- benzoyl-7-chloro-1,2-dihydro-3 methylaminoquinoxaline, lactose and corn starchwere' mixed in a suitable mixer. The mixture was further blended. by passing through a Fitzpatrick Comminuting Machine with a No. 1A screen with knives forward. The blended powder was returned to the mixer, the talcadded and blended thoroughly. The mixture was filled into No. 4 hard shell gelatin capsules on a Parke Davis capsulatingmachine. (Any similar type capsulating machine may be used.)

I "Exampre 4 f capsule was prepa i'ed in' same manner as Example 3 except that 9 chloro-5-methylamino-2- phehyl-4H-1,3,5 benzox'adiazocine' was the active ingre- Example 5 I 1-be'nz'oyl-7-chloro -1,2 diliydr'o 3"- methylaminoquirioxalir1e5 .0 mg.

Propylene glycol0.4 cc.

Benzyl alcohol (benzaldehyde free)0.015 cc.

Ethanol percent USP0.10 cc.

Sodium benzoate-48.8 mg.

Benzoic acid-1.2 mg.

Water for injection--l.0 cc.

A 1,000 cc. parenteral formulation was prepared as follows: The 50 grams of 1-benzoyl-7-chloro-1,2-dihydro-3- methylaminoquinoxaline were dissolved in cc. of benzyl alcohol; 4,000 cc. of propylene glycol and 1,000 cc. of ethanol were added. The 12 grams of benzoic acid were dissolved in the above. The 488 grams of sodium benzoate dissolved in 3,000 cc. of water for injection were added. The solution was brought up to final volume of 10,000 cc. with water for injection. The solution was filtered through an 02 Selas candle, filled into suitable size ampules, gassed with N and sealed. It was then autoclaved at 10 p.s.i. for 30 minutes.

Example 6 quinoxaline 25.00 Dicalcium phosphate dihydrate, uumilled 175.00 Corn starch 24.00 Magnesium stearate 1.00

Total weight 225.00

A 225 mg. tablet was prepared according to the following procedure: 1-benzoyl-7-chloro-1,2-dihydro-3-methylaminoquinoxaline and corn starch were mixed together and passed through a No. 00 screen in Model J Fitz with hammers forward, This premix was then mixed with dicalcium phosphate and one-half of the magnesium stearate, passed through a No. 1A screen in Model I Fitz with knives forward and slugged. The slugs were passed through a No. 2A plate in a Model D Fitz at slow speed with knives forward, and the remaining magnesium stearate was added. The mixture was mixed and compressed.

Example 8 A 225 mg. tablet was prepared in the same manner as Example 7, except that 9-chloro-S-methylamino-Z-phenyl- 4H-1,3,5-benzoxadiazocine was the active ingredient.

t 7 We claim: 1. A compound of the formula:

CRi R CH-Rz =0 is wherein R is selected from the group consisting of hydrogen, lower alkyl, halogen, nitro, and trifluoromethyl; R is selected from the group NR R hydrogen and lower alkyl; R is selected from the group consisting of hydrogen, lower alkyl and lower alkoxy-lo'wer alkyl; R, is selected from the group consisting of phenyl, 'and phenyl substituted in the 2-position with chlorine or fluorine; and R and R are selected from the group consisting of hydrogen and lower alkyl and R and R ta'lgen together with' their attached nitrogen atoni fo 'r'm a'p'yrrolidin'o' or *pip'eridino ring; and .pharmaceutically acceptable salts thereof.

.2. The compound of claim'l wherein R is i Y B4 7 wherein R and- R are as above.

The-'comp'ound of claim 2 wherein said compound is l-behzoyl-V-chlOrO-l;2 dihydro-3 methylamino quinoxazoline; V i

r Noreferences'cited. 1

NICHOLAS s; RI ZZO, Primary Examiner I 

